1. Field of the Invention
The present invention relates to a tricyclic triazolobenzazepine derivative having antiallergic activity as a prodrug, an intermediate for synthesizing the same, a process for producing the same, and an antiallergic agent.
2. Background Art
In recent years, it has been revealed that allergic reactions induced by various stimuli such as immunoreactions can be divided into two reactions, i.e., an immediate reaction which occurs immediately after the stimulation and a delayed reaction which occurs several hours after the stimulation (see, for example, xe2x80x9cLaie Asthmatic Responsesxe2x80x9d, P. M. O""byrne, J. Dolovich and F. E. Hargreave, Am. Rev. Respir. Dis., 1987; 136: 740-751). Especially, the control of the latter reaction has become important.
Clinical studies show that there are few drugs which are significantly effective in inhibiting the delayed allergic reaction. Thus, the development of drugs therapeutically effective in treating both the immediate reaction and the delayed reaction has been expected in the art.
Sodium cromoglicate has been known as a representative drug for inhibiting the immediate and delayed allergic reactions. This drug is clinically administered by inhalation because it is not useful when orally administered.
The administration by inhalation, however, is disadvantageous in that it is difficult to properly administer the drug to babies, infants, and children and that it is difficult to continuously administer the drug to patients who are highly sensitive to inhalation stimuli.
Thus the development of oral drugs which can inhibit both the immediate and delayed allergic reactions and have excellent efficacy have been expected in the art.
In recent years, many studies on antiallergic agents and therapeutic agents for asthma have been conducted in the art. Tricyclic compounds containing seven membered ring which have been studied include dibenzoxepine derivatives (Japanese Patent Laid-Open Nos. 10784/1988 and 78292/1993 and Journal of Chemical and Pharmaceutical Bulletin, vol. 39, No. 10, p. 2724 and p. 2729 (1991)), dibenzoxazepine derivatives (Japanese Patent Laid-Open Nos. 184963/1991, 211071/1992, and 65257/1993 and EP 5180720), and dibenzocycloheptene derivatives (WO 93/13068). Further, tricyclic benzazepine derivatives and tricyclic benzothiazepine derivatives are disclosed in EP 0686636, WO 95/18130, and WO 97/00258.
Meanwhile, a prodrug technique has been known as one means for improving the bioavailability of a drug (Keiko Toyo Seizai No Sekkei To Hyoka (Design and Assay of Oral Preparation): edited by Mitsuru Hashida, Yakugyo Jiho Co., Ltd., pp. 216-231 (1995)). Chemical modification of a carboxyl, hydroxyl, amino or other group of the drug through an ester, amido, acetal or other bond can improve the bioavailability of the drug. However, any 1,2,3-triazole-modified prodrug has not been reported in the art.
The present inventors have synthesized a tricyclic triazolobenzazepine derivative having a chemically modified triazole ring and have found that the derivative has superior. bioavailability compared with the corresponding triazolobenzazepine.
In one aspect of the present invention, there are provided tricyclic triazolobenzazepine derivatives as a prodrug represented by formula (I) and pharmacologically acceptable salts and solvates thereof: 
wherein
R1 represents a hydrogen atom, a hydroxyl group, C1-4 alkyl, or phenyl C1-4 alkyl;
R2, R3, R4, and R5, which may be the same or different, represent any one of the following (a) to (n):
(a) a hydrogen atom;
(b) a halogen atom;
(c) an optionally protected hydroxyl group;
(d) formyl;
(e) C1-12 alkyl which may be substituted by a halogen atom;
(f) C2-12 alkenyl which has one or more carbonxe2x80x94carbon double bonds and may be substituted by
(1) a halogen atom,
(2) cyano,
(3) xe2x80x94COR9 wherein R9 represents a hydrogen atom or C1-6 alkyl,
(4) xe2x80x94COOR10 wherein R10 represents a hydrogen atom or C1-6 alkyl,
(5) xe2x80x94CONR11R12 wherein R11 and R12, which may be the same or different, represent
(i) a hydrogen atom,
(ii) C1-6 alkyl which may be substituted by amino optionally substituted by C10-4 alkyl, phenyl optionally substituted by C1-4 alkyl which may be substituted by a saturated five- to seven-membered heterocyclic ring containing one or two nitrogen atoms (the nitrogen atoms may be substituted by C1-4 alkyl), or a saturated or unsaturated five- to seven-membered heterocyclic ring,
(iii) phenyl which may be substituted by carboxyl, or
(iv) a saturated or unsaturated five to seven-membered heterocyclic ring,
(6) a saturated or unsaturated five- to seven-membered heterocyclic ring which may be substituted by C1-4 alkyl or may form a bicyclic ring fused with another ring;
(g) C1-12 alkoxy which may be substituted by
(1) a halogen atom,
(2) a hydroxyl group,
(3) cyano,
(4) C3-7 cycloalkyl,
(5) phenyl,
(6) C1-4 alkoxy,
(7) phenoxy,
(8) amino which may be substituted by C1-4 alkyl,
(9) xe2x80x94COR13 wherein R13 represents a hydrogen atom, C1-6 alkyl, phenyl optionally substituted by a halogen atom or C1-4 alkoxy, or phenyl C1-4 alkyl,
(10) xe2x80x94COOR14 wherein R14 represents a hydrogen atom or C1-6 alkyl,
(11) xe2x80x94CONR15R16 wherein R15 and R16, which may be the same or different, represent a hydrogen atom or C1-6 alkyl which may be substituted by a saturated or unsaturated five- to seven-membered heterocyclic ring, or
(12) a saturated or unsaturated five- to seven-membered heterocyclic ring which may be substituted by C1-4 alkyl or phenyl C1-4 alkyl;
(h) xe2x80x94Cxe2x95x90Nxe2x80x94OR16 wherein R16 represents a hydrogen atom, C1-6 alkyl, phenyl C1-4 alkyl, or phenyl;
(i) xe2x80x94(CH2)mOR17 wherein m is an integer of 1 to 4, and R17 represents a hydrogen atom, C1-6 alkyl, or phenyl C1-4 alkyl of which one or more hydrogen atoms on the benzene ring may be substituted by C1-4 alkyl;
(j) xe2x80x94(CH2)kxe2x80x94COR18 wherein k is an integer of 1 to 4, and R18 represents a hydrogen atom or C1-4 alkyl;
(k) xe2x80x94(CH2)jxe2x80x94COOR19 wherein j is an integer of 0 to 4, and R19 represents a hydrogen atom or C1-6 alkyl;
(l) xe2x80x94(CH2)pxe2x80x94NR20R21 wherein p is an integer of 1 to 4, and R20 and R21, which may be the same or different, represent
(1) a hydrogen atom,
(2) C1-6 alkyl which may be substituted by amino optionally substituted by C1-4 alkyl,
(3) phenyl C1-4 alkyl,
(4) xe2x80x94COR22 wherein R22 represents a hydrogen atom or C1-4 alkyl which may be substituted by carboxyl, or
(5) xe2x80x94SO2R23 wherein R23 represents C1-4 alkyl or phenyl which may be substituted by a halogen atom;
(m) xe2x80x94(CH2)qxe2x80x94CONR24R25 wherein q is an integer of 0 to 4, and R24 and R25, which may be the same or different, represent a hydrogen atom, a saturated or unsaturated five- to seven-membered heterocyclic ring, or C1-6 alkyl which may be substituted by a saturated or unsaturated five- to seven-membered heterocyclic ring, or alternatively R24 and R25 may form a saturated or unsaturated five- to seven-membered heterocyclic ring together with a nitrogen atom to which they are attached (the heterocyclic ring may further contain at least one oxygen, nitrogen, or sulfur atom, may form a bicyclic ring fused with another ring, or may be substituted by C1-4 alkyl); and
(n) xe2x80x94NR26R27 wherein R26 and R27, which may be the same or different, represent a hydrogen atom or xe2x80x94COR28 wherein R28 represents a hydrogen atom, C1-6 alkyl, or phenyl which may be substituted by C1-4 alkyl or C1-6 alkoxy optionally substituted by phenyl;
R31 and R32, which may be the same or different, represent a hydrogen atom or C1-6 alkyl which may be substituted by a halogen atom; and
Q represents a group selected from the following groups (i) to (iv) or a halogen atom or C1-6 alkoxy: 
xe2x80x83wherein
R33 represents
C1-6 alkyl which may be substituted by C1-6 alkoxy optionally substituted by C1-6 alkoxy, phenyl optionally substituted by C1-6 alkoxy, amino, or nitro, or a saturated or unsaturated five- to seven-membered heterocyclic ring optionally substituted by C1-6 alkoxy, amino, or nitro,
phenyl which may be substituted by C1-6 alkoxy, amino, or nitro, or
a saturated or unsaturated five- to seven-membered heterocyclic ring which may be substituted by C1-6 alkoxy, amino, or nitro, or
R33 may form C1-4 alkylene together with R31 or R32,
R34 represents
C1-6 alkyl which may be substituted by a halogen atom, carboxyl, phenyl optionally substituted by C1-6 alkoxy, amino, or nitro, or a saturated or unsaturated five- to seven-membered heterocyclic ring optionally substituted by C1-6 alkoxy, amino, or nitro,
phenyl which may be substituted by C1-6 alkoxy, amino, or nitro, or
a saturated or unsaturated five- to seven-membered heterocyclic ring which may be substituted by C1-6 alkoxy, amino, or nitro,
R35 and R36, which may be the same or different, represent a hydrogen atom or C1-6 alkyl which may be substituted by amino optionally substituted by C1-4 alkyl or
R35 and R36 may form a saturated or unsaturated five- to seven-membered heterocyclic ring together with a nitrogen atom to which they are attached, and
R37 and R38, which may be the same or different, represent C1-6 alkyl.
In another aspect of the present invention, there are provided tricyclic benzazepine derivatives as a prodrug represented by formula (Ia) and pharmacologically acceptable salts and solvates thereof: 
wherein
R41 and R42, which may be the same or different, represent a hydrogen atom, optionally protected hydroxyl, C1-6 alkoxy which may be substituted by a halogen atom, or C1-6 alkyl which may be substituted by a halogen atom and
R31, R32, and Q are as defined above.
The tricyclic triazolobenzazepine derivatives according to the present invention are useful for the treatment of allergic diseases.
In another aspect of the present invention, there is provided a pharmaceutical composition comprising as an active ingredient the compound represented by formula (I) or (Ia) or a pharmacologically acceptable salt or a solvate thereof.
In a further aspect of the present invention, there are provided intermediates for synthesizing the compounds represented by formulae (I) and (Ia).
Specifically, an intermediate according to the present invention is a compound represented by formula (II) or a salt or solvate thereof: 
wherein R51 represents nitro or amino, R52 represents a hydrogen atom or a protective group for carboxyl, and Q, R2 to R5, R31, and R32 are as defined above.
Another intermediate according to the present invention is a compound represented by formula (IIxe2x80x2) or a salt or solvate thereof: 
wherein Q, R2 to R5, R31, R32, R51, and R52 are as defined above.
A further intermediate according to the present invention is a compound represented by formula (VI) or a salt or solvate thereof: 
wherein Q, R2 to R5, R31, R32, and R52 are as defined above.
A further intermediate according to the present invention is a compound represented by formula (VIxe2x80x2) or a salt or solvate thereof: 
wherein Q, R2 to R5, R31, R32, and R52 are as defined above.
A further intermediate according to the present invention is a compound represented by formula (VII) or a salt or solvate thereof: 
wherein R2 to R5, and R52 are as defined above.
A further intermediate according to the present invention is a compound represented by formula (VIII) or a salt or solvate thereof: 
wherein R61 represents a protective group for triazole and R2 to R5, and R52 are as defined above.
A further intermediate according to the present invention is a compound represented by formula (IXa) or a salt or solvate thereof: 
wherein R41 to R42, and R52 are as defined above, provided that R41 and/or R42 do not represent a hydrogen atom.
A further intermediate according to the present invention is a compound represented by formula (XVIa) or a salt or solvate thereof: 
wherein R41 to R42, R51, and R52 are as defined above.
These intermediates are useful in producing the compound s represented by formulae (I) and (Ia).
Definition
As used herein, the term xe2x80x9calkylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as a group or a part of a group means straight-chain, branched, or cyclic alkyl or alkoxy.
C1-6 alkyls as used herein include straight-chain alkyls such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl, branched alkyls, such as isopropyl, isobutyl, tert-butyl, and 3-pentyl, and cyclic alkyls, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
C1-6 alkoxys as used herein include straight-chain alkoxys having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, and n-hexyloxy, branched alkoxys, such as isopropyloxy, isobutyloxy, and tert-butyloxy, and cyclic alkoxys, such as cyclopropyloxy and cyclohexyloxy.
C1-6 alkyls as used herein include, in addition to the above C1-6 alkyls, alkyls having 7 to 16 carbon atoms, such as 1-methylhexyl, 5-methylhexyl, heptyl, octyl, nonyl, decyl, undecyl, and pentadecyl.
The term xe2x80x9chalogen atomxe2x80x9d as used herein means a fluorine, chlorine, bromine, or iodine atom.
The term xe2x80x9cdissimilar atomxe2x80x9d as used herein means an oxygen, nitrogen, or sulfur atom.
The term xe2x80x9csaturated or unsaturated five- to seven-membered heterocyclic ringxe2x80x9d as used herein means a heterocycle containing one or more heteroatoms selected from oxygen, nitrogen, and sulfur atoms. Examples of heterocyclic rings include pyridine, imidazole, oxazole, thiazole, pyrimidine, furan, thiophene, pyrrole, pyrrolidine, piperidine, tetrahydrofuran, and oxazoline.
Compounds
In formula (I), R2, R3, R4, and R5 each independently represent any one of groups (a) to (n).
Examples of protective groups for the hydroxyl group (c) include acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, benzoyl, 4-nitrobenzoyl, 3-oxobutyryl, benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, methoxymethyl, methoxyethoxymethyl, benzyloxymethyl, trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, 2-tetrahydropyranyl, and trimethylsilylethoxymethoxy.
(e) C1-12 alkyl is preferably C1-6 alkyl, more preferably C1-4 alkyl.
(f) C2-12 alkenyl is preferably C2-6 alkenyl, more preferably C2-4 alkenyl, most preferably vinyl.
At least one hydrogen atom on the alkenyl may be substituted by (1) a halogen atom, (2) cyano, (3) xe2x80x94COR9, (4) xe2x80x94COOR10, (5) xe2x80x94CONR11R12, or (6) a saturated or unsaturated five- to seven-membered heterocyclic ring.
In (5) xe2x80x94CONR11R12, R11 and R12, which may be the same or different, represent a hydrogen atom or C1-6 alkyl (preferably C1-4 alkyl), phenyl, or a saturated or unsaturated five- to seven-membered heterocyclic ring.
In this case, this alkyl may be further substituted by amino, phenyl, or a saturated or unsaturated five- to seven-membered heterocyclic ring.
Further, one or two hydrogen atoms on this amino may be substituted by C1-4 alkyl.
This phenyl may also be substituted by C1-4 alkyl. In this case, this C1-4 alkyl may be substituted by a saturated five- to seven-membered heterocyclic ring containing one or two nitrogen atoms optionally substituted by C1-4 alkyl. Preferred examples thereof include piperidino, 4-piperidyl, 1-pyrrolidinyl, piperazinyl, 4-C1-4 alkylpiperazinyl, and morpholino.
(g) C1-12 alkoxy is preferably C1-6 alkoxy, more preferably C1-4 alkoxy.
This alkoxy may be substituted by (9) xe2x80x94COR13 wherein R13 represents a hydrogen atom, C1-6 alkyl (preferably C1-4 alkyl), phenyl, or phenyl C1-4 alkyl. In this case, this phenyl may be substituted by a halogen atom or C1-4 alkoxy. Although the position of the substituent is not particularly limited, the 2- or 4-position on the phenyl ring is preferred.
(g) C1-12 alkoxy may be substituted by a saturated or unsaturated five- to seven-membered heterocyclic ring as substituent (12). This heterocyclic ring is preferably a five- or six-membered heterocyclic saturated ring containing one or two nitrogen atoms, for example, piperidino, 4-piperidinyl, 1-pyrrolidinyl, piperazinyl, and morpholino. One or more hydrogen atoms on the heterocyclic ring may be further substituted by C1-4 alkyl or phenyl C1-4 alkyl. Preferred examples of phenyl C1-4 alkyls include benzyls, such as benzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-hydroxybenzyl, 4-nitrobenzyl, 4-methoxybenzyl, and 4-carboxybenzyl, phenethyl, 3-phenylpropyl, and 4-phenylbutyl.
In (i) xe2x80x94(CH2)mOR17, is an integer of 1 to 4, preferably an integer of 1 or 2.
In (j) xe2x80x94(CH2)kCOR18, k is an integer of 0 to 4, preferably 0, 1, or 2.
In (k) xe2x80x94(CH2)jCOOR19, j is an integer of 0 to 4, preferably 0, 1, or 2.
In (m) xe2x80x94(CH2)qCONR24R25, q is an integer of 0 to 4, preferably 0, 1, or 2.
R24 and R25 may form a saturated or unsaturated five- to seven-membered heterocyclic ring together with a nitrogen atom to which they are attached. This heterocyclic ring may further contain one or more oxygen, nitrogen, or sulfur atoms. The heterocyclic ring may be substituted by C1-4 alkyl. Preferred examples of heterocyclic ring include piperazino, piperidino, N-methylpiperazino, morpholino, succinimide, indolyl, 4-methylindolyl, 5-methylindolyl, isoindolyl, phthalimido, 4-methylphthalimido, and 1,1-dioxo-2-benzothiazolyl.
In formulae (I) and (Ia), Q may represent a halogen atom, C1-6 alkoxy (preferably C1-4 alkoxy), or any one of groups (i) to (iv).
In group (i), one or more hydrogen atoms on this C1-6 alkyl represented by R33 may be substituted by C1-6 alkoxy, phenyl, or a saturated or unsaturated five- to seven-membered heterocyclic ring (preferably a six-membered heterocycle containing one hetero atom). Further, one or more hydrogen atoms on this C1-6 alkoxy may be substituted by C1-6 alkoxy. One or more hydrogen atoms on this phenyl and the heterocyclic ring may be substituted by C1-6 alkoxy, amino, or nitro.
Preferred examples of C1-6 alkyls represented by R33 include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, tert-butyl, 3-pentyl, cyclopropyl, cyclobutyl, ,cyclopentyl, cyclohexyl, 1,3-diethoxy-2-propyl, 2-isopropoxyethyl, phenethyl, 3-pyridylmethyl, 4-methoxyphenethyl, and 2-(2-methoxyethoxy)ethoxy.
R33 may represent phenyl. This phenyl may be substituted by C1-6 alkoxy, amino, or nitro, preferably nitro. Preferred examples of phenyls represented by R33 include 4-nitrophenyl.
Further, R33 may represent a saturated or unsaturated five- to seven-membered heterocyclic ring (preferably a six-membered heterocycle containing one hetero atom). At least one hydrogen atom on the heterocyclic ring may be substituted by C1-6 alkoxy, amino, or nitro, preferably nitro. Preferred examples of saturated or unsaturated five- to seven-membered heterocyclic ring represented by R33 include 4-piperazyl, 4-piperidyl, and 4-tetrahydropyranyl.
Further, R33 may form C1-4 alkylene together with any one of R31 and R32. Preferred examples of C1-4 alkylenes include methylene. When R33 forms methylene together with R31 or R32 and R31 or R32 which is not bonded to R33 represents a hydrogen atom, then xe2x80x94CQR31R32 represents 4-(2-oxo)-1,3-dioxolyl.
In group (ii), one or more hydrogen atoms on C1-16 alkyl represented by R34 may be substituted by a halogen atom, carboxyl, phenyl, or a saturated or unsaturated five- to seven-membered heterocyclic ring (preferably a six-membered heterocyclic ring containing one hetero atom). Further, one or more hydrogen atoms on the phenyl and the heterocycle may be substituted by C1-6 alkoxy, amino, or nitro
Preferred examples of C1-16 alkyls represented by R34 include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, tert-butyl, 3-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylhexyl, 5-methylhexyl, heptyl, octyl, nonyl, decyl, undecyl, pentadecyl, chloromethyl, 3-chloropropyl, 2-carboxyethyl, morpholinomethyl, 4-methoxybenzyl, and 4-piperazinylmethyl.
R34 may represent phenyl. The phenyl may be substituted by C1-6 alkoxy, amino, or nitro, preferably amino. Preferred examples of phenyls represented by R34 include 4-aminophenyl.
Further, R34 may represent a saturated or unsaturated five- to seven-membered heterocyclic ring (preferably a six-membered heterocyclic ring containing one hetero atom). One or more hydrogen atoms on the heterocyclic ring may be substituted by C1-6 alkoxy, amino, or nitro, preferably amino. Preferred examples of saturated or unsaturated five- to seven-membered heterocyclic rings represented by R34 include 3-pyridyl and 4-pyridyl.
In group (iii), one or more hydrogen atoms on C1-6 alkyl represented by R35 and R36 may be substituted by amino. Preferred examples of C1-6 alkyls represented by R35 and R36 include 2-(N,N-dimethylamino) ethyl. Preferred examples of saturated or unsaturated five- to seven-membered heterocyclic rings formed by combining R35 with R36 include 1-morpholino, 1-imidazolyl, and 4-piperazinyl.
A group of preferred compounds represented by formula (I) include:
a group of compounds wherein R1, R2, R3, R4, and R5 represent a hydrogen atom or (g) C1-12 alkoxy (preferably C1-6 alkoxy) and Q represents group (i) (preferably R33 represents C1-4 alkyl optionally substituted by C1-4 alkoxy);
a group of compounds wherein R1 represents a hydrogen atom, R2, R3, R4, and R5 represent a hydrogen atom or (g) C1-12 alkoxy (preferably C1-6 alkoxy), and Q represents group (i) (preferably, R33 represents C1-4 alkyl optionally substituted by C1-4 alkoxy);
a group of compounds wherein R1, R2, and R5 represents a hydrogen atom, R3 and R4 represent a hydrogen atom or (g) C1-12 alkoxy (preferably C1-6 alkoxy), and Q represents group (i) (preferably, R33 represents C1-4 alkyl optionally substituted by C1-4 alkoxy);
a group of compounds wherein R1, R2, and R5 represent a hydrogen atom, R3 and R4 represent a hydrogen atom or (f) C2-12 alkenyl, and Q represents group (i) (preferably, R33 represents C1-4 alkyl optionally substituted by C1-4 alkoxy);
a group of compounds wherein R1, R2, and R5 represent a hydrogen atom, R3 and R4 represent a hydrogen atom or (e) C1-12 alkyl, and Q represents group (i) (preferably, R33 represents C1-4 alkyl optionally substituted by C1-4 alkoxy);
a group of compounds wherein R1, R2, and R5 represent a hydrogen atom, R3 and R4 represent a hydrogen atom, or (j) group xe2x80x94(CH2)kCOR18, (l) xe2x80x94(CH2)pNR20R21, (m) xe2x80x94(CH2)qCONR22R23, or (n) xe2x80x94NR29R30, and Q represents group (i) (preferably, R33 represents C1-4 alkyl optionally substituted by C1-4 alkoxy);
a group of compounds wherein R1, R2, R4, and R5 represent a hydrogen atom, R3 represents (g) C1-12 alkoxy (preferably C1-6 alkoxy), and Q represents group (i) (preferably, R33 represents C1-4 alkyl optionally substituted by C1-4 alkoxy); and
a group of compounds wherein R1, R2, R3, and R5 represent a hydrogen atom, R4 represents (g) C1-12 alkoxy (preferably, C1-6 alkoxy), and Q represents group (i) (preferably, R33 represents C1-4 alkyl optionally substituted by C1-4 alkoxy).
In formulae (I) and (Ia), xe2x80x94CR31R32Q is preferably located at the 2-position in the triazole ring.
One or more hydrogen atoms on C1-6 alkyl represented by R31 and R32 in formulae (I) and (Ia) and one or more hydrogen atoms on the C1-6 alkyl and the C1-6 alkoxy in its alkyl portion represented by R41 and R42 in formula (Ia) may be substituted by a halogen atom. Examples of the substituted alkyls and alkyl portions include trifluoromethyl, 2-fluoroethyl, difluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, 2-chloroethyl, dichloromethyl, 2,2,2-trichloroethyl, tribromomethyl, 2-bromoethyl, dibromomethyl, 2,2,2-tribromoethyl, pentafluoroethyl, fluoromethyl, 3,3,3-trifluoropropyl, 4,4,4-trichlorobutyl, 5,5,5-trifluoropentyl, and 6,6,6-trifluorohexyl.
Protective groups for optionally protected hydroxyl which may be represented by R41 and R42 include acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, benzoyl, 4-nitrobenzoyl, 3-oxobutyryl, benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, methoxymethyl, methoxyethoxymethyl, benzyloxymethyl, trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl, 2-tetrahydropyranyl, and trimethylsilylethoxymethoxy.
R41 and R42 represent preferably C1-4 alkoxy, more preferably methoxy or isopropyloxy. Still more preferably, R41 represents methoxy, and R42 represents methoxy or isopropyloxy.
A group of preferred compounds represented by formula (Ia) include a group of compounds wherein R41 and R42 represent C1-6 alkoxy (preferably C1-4 alkoxy, more preferably methoxy or isopropyloxy), and Q represents group (i) (preferably, R33 represents optionally C1-4 alkoxy-substituted C1-4 alkyl).
Among the compounds according to the present invention, particularly preferred compounds include
2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7,8-dimethoxy-4 (5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine,
2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-7,8-dimethoxy-4 (5H), 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine,
2-(1-(1,3-diethoxy-2-propoxycarbonyloxy)-2-methylpropyl)-8-isopropoxy-7-methoxy-4 (5H),10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine, and
8-isopropoxy-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-7-methoxy-4 (5H) 10-dioxo-2H-1,2,3-triazolo[4,5-c][1]benzazepine.
In the present invention, protective groups for carboxyl represented by R52 include, for example, methyl, ethyl, tert-butyl, benzyl, 4-methoxybenzyl, diphenylmethyl, 4-nitrobenzyl, tert-butyldimethylsilyl, triphenylsilyl, 2-phenylsulfonylethyl, 2-methoxycarbonylethyl, 2-cyanoethyl, and 2-trimethylsilylethyl.
In the present invention, xe2x80x9cprotective groups for triazolexe2x80x9d represented by R61 include, for example, benzyl optionally substituted by a halogen atom, hydroxyl, nitro, C1-6 alkyl, or C1-6 alkoxy, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, benzyloxymethyl, and methoxyethoxy.
A group of preferred intermediate compounds represented by formulae (II), (IIxe2x80x2), (VI), and (VIxe2x80x2) include compounds wherein, R2 and R5 represent a hydrogen atom, R3 and R4 each independently represent a hydrogen atom, optionally protected hydroxyl, optionally substituted C1-6 alkoxy, optionally substituted C1-6 alkyl (preferably, optionally substituted C1-6 alkoxy), and Q represents group (i) (preferably, R33 represents C1-4 alkyl optionally substituted by C1-4 alkoxy).
A group of preferred intermediate compounds represented by formulae (VII) and (VIII) include compounds wherein R2 and R5 represent a hydrogen atom and R3 and R4 each independently represent a hydrogen atom, optionally protected hydroxyl, optionally substituted C1-6 alkoxy, and optionally substituted C1-6 alkyl (preferably, optionally substituted C1-6 alkoxy).
Preferred examples of compounds represented by formulae (VI) and (VIxe2x80x2) include
ethyl 5-(3,4-dimethoxybenzoyl)-2-(1-isopropoxycarbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate,
ethyl 2-(1-isopropoxycarbonyloxy-2-methylpropyl)-5-(3-isopropoxy-4-methoxybenzoyl)-2H-1,2,3-triazole-4-carboxylate,
ethyl 5-(3,4-dimethoxybenzoyl)-2-(1-(1,3-diethoxy-2-propoxy) carbonyloxy-2-methylpropyl)-2H-1,2,3-triazole-4-carboxylate, and
ethyl 2-(1-(1,3-diethoxy-2-propoxy)carbonyloxy-2-methylpropyl)-5-(3-isopropoxy-4-methoxybenzoyl)-2H-1,2,3-triazole-4-carboxylate.
Examples of preferred compounds represented by formula (VII) include
methyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate,
ethyl 5-(3,4-dimethoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate,
methyl 5-(3-isopropoxy-4-methoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate, and ethyl 5-(3-isopropoxy-4-methoxybenzoyl)-1H-1,2,3-triazole-4-carboxylate.
Examples of preferred compounds represented by formula (IX) include
methyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butynoate,
ethyl 4-(3,4-dimethoxyphenyl)-4-oxo-2-butynoate,
methyl 4-(3-isopropoxy-4-methoxyphenyl)-4-oxo-2-butynoate, and
ethyl 4-(3-isopropoxy-4-methoxyphenyl)-4-oxo-2-butynoate.
Examples of preferred compounds represented by formula (XVI) include ethyl 4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butynoate and ethyl 4-(5-isopropoxy-4-methoxy-2-nitrophenyl)-4-oxo-2-butynoate.
In the compounds according to the present invention, tautomers and position isomers derived from triazole ring, cis-trans isomers derived from alkenyl as the substituent, and enantiomers derived from the group xe2x80x94CQR33R34 may exist, and any of the isomers and a mixture thereof fall within the scope of the present invention.
The compounds according to the present invention may be formed into pharmacologically acceptable salts thereof. Such salts include non-toxic salts. Preferred salts include alkali metal or alkaline earth metal salts, such as sodium, potassium, and calcium salts, hydrohalogenic acid salts, such as hydrofluoride salts, hydrochloride salts, hydrobromide salts, and hydroiodide salts, inorganic acid salts, such as nitric acid salts, perchloric acid salts, sulfuric acid salts, and phosphoric acid salts, lower alkylsulfonic acid salts, such as methanesulfonic acid salts, trifluoromethanesulfonic acid salts, and ethanesulfonic acid salts, arylsulfonic acid salts, such as benzenesulfonic acid salts and p-toluenesulfonic acid salts, organic acid salts, such as fumaric acid salts, succinic acid salts, citric acid salts, tartaric acid salts, oxalic acid salts, and maleic acid salts, and amino acid salts, such as glutamic acid salts and aspartic acid salts.
Solvates of the compounds according to the present invention include hydrates and ethanol solvates.
Production of compounds
The compounds according to the present invention may be synthesized by the following process 1 or 2.
 less than Process 1 greater than 
The compound represented by formula (I) may be produced by reacting a compound represented by formula (III) 
wherein R1 to R5 are as defined above, with a compound represented by formula (IV) 
wherein Q, R31 and R32 are as defined above and Hal represents a halogen atom, in a solvent which is not involved in the reaction (for example, water, ethanol, isopropyl alcohol, tetrahydrofuran, diisopropyl ether, methylene chloride, acetone, N,N-dimethylformamide, dimethylsulfoxide) in the presence of a base at a temperature of 0 to 150xc2x0 C. for 1 to 48 hr. Bases as used herein include organic bases such as pyridine and triethylamine, and inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium hydroxide, and potassium hydroxide. Preferably, the compound may be prepared by the reaction in N,N-dimethylformamide in the presence of sodium hydrogencarbonate at a reaction temperature of 20 to 100xc2x0 C. for 1 to 24 hr. The compound represented by formula (I) is produced as a mixture of a 1-substituted triazole, a 2-substituted triazole, and a 3-substituted triazole in any ratio.
The compound represented by formula (III) may be produced by processes described, for example, in WO 95/18130 and WO 97/00258.
The compound represented by formula (I) may be purified by conventional purification methods, for example, recrystallization, reprecipitation, solvent extraction, column chromatography on silica gel, or column chromatography on adsorptive resin.
 less than Process 2 greater than 
The compound represented by formula (I) may be produced by reducing the compound of formula (IIa) 
wherein Q, R2 to R5, R31, R32, and R52 are as defined above, to prepare a compound represented by formula (IIb) 
wherein Q, R2 to R5, R31, R32, and R52 are as defined above, and then cyclizing the compound represented by formula (IIb).
Conventional catalytic reductions (preferably in the presence of a nickel or palladium catalyst in a solvent, for example, ethyl acetate, an alcohol solvent such as ethanol, water, or a mixture thereof) or reduction using a metal such as iron or zinc, for example, reduction in a zinc-acetic acid system, and the like may be used for the reduction reaction. The reduction may be carried out at a temperature of 10 to 100xc2x0 C. for 0.1 to 10 hr.
The cyclization may be carried out by reacting the compound represented by formula (IIb) with a strong base such as sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, or potassium tert-butoxide, in a solvent which is not involved in the reaction (for example, an alcohol such as methanol, ethanol, or isopropyl alcohol, toluene, N,N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, or a mixture of two or more of these solvents) at a temperature of 0 to 100xc2x0 C. for 1 to 48 hr, generally 5 to 24 hr.
The cyclization reaction may also be carried out in an acetic acid or trifluoroacetic acid solvent by reacting the compound represented by formula (IIb) at a temperature of 20 to 100xc2x0 C. for 1 to 24 hr.
After the cyclization, Q may be further converted to another substituent.
In both the above reduction and cyclization reactions, the position isomerization of the substituent on the triazole is not observed. When a compound represented by formula (IIaxe2x80x2) is used alone, the compound represented by formula (I) is obtained as a single compound.
The compound represented by formula (I) may be purified by conventional purification methods, for example, recrystallization, reprecipitation, solvent extraction, column chromatography on silica gel, or column chromatography on adsorptive resin.
The compound represented by formula (IIa) may be synthesized according to the following scheme. In the scheme, M represents lithium, magnesium chloride, magnesium bromide, magnesium iodide, zinc bromide, zinc iodide, cadmium bromide, cadmium iodide, or copper, R62 represents sodium, C1-6 alkylsilyl (for example, trimethylsilyl), or C1-6 alkyltin, and Q, Hal, R2 to R5, R31, R32, R52, and R61 are as described above. 
The compound represented by formula (IIa) may be produced from a compound represented by formula (V) by the following process A, B, C or D. According to the process B, C, or D, the compound represented by formula (IIa) having the substituent xe2x80x94CQR31R32 (represented by formula (IIaxe2x80x2)) can be prepared, wherein the substituent is introduced into the triazole ring at its 2-position.
 less than Process A greater than 
The compound represented by formula (IIa) may be prepared by reacting the compound represented by formula (V): 
wherein Q, R2 to R5, and R52 are as defined above, with the compound represented by formula (IV) according to process 1. As with the compound (I) prepared by process 1, the compound represented by formula (IIa) thus prepared is a mixture of three types of isomers. For example, the compound represented by formula (V) may be prepared in accordance with a process described in WO 95/18130.
 less than Process B greater than 
wherein Q, R2 to R5, R31, R32, and R52 are as defined above.
The compound represented by formula (V) is reacted with a ketone or an aldehyde represented by R31R32Cxe2x95x90O in a solvent which is not involved in the reaction (for example, methylene chloride, ethyl acetate, or acetonitrile) at a temperature of xe2x88x9278 to 100xc2x0 C., preferably xe2x88x9220 to 50xc2x0 C. for 0.1 to 24 hr, generally 0.1 to 1 hr. In this case, a hemiacetal represented by the compound (Vxe2x80x2) is produced in the reaction system. This reaction is promoted by the addition of an acid catalyst. Preferred acid catalysts used herein include protonic acids such as p-toluenesulfonic acid, pyridinium salt of p-toluenesulfonic acid, D-(+)-camphorsulfonic acid, trifluoroacetic acid, sulfuric acid, hydrochloric acid, perchloric acid and phosphoric acid, and Lewis acids, such as boron trifluoride-diethyl ether complex, aluminum chloride, and titanium tetrachloride.
Q in formula (IIaxe2x80x2) may be introduced by further adding various reactants to the compound represented by formula (Vxe2x80x2). The compound represented by formula (IIaxe2x80x2) wherein Q is any one of groups (i) to (iv), a halogen atom, or a C1-6 alkoxy may be synthesized in accordance with the following.
(1) The compound represented by formula (IIaxe2x80x2) wherein Q is group (i) may be prepared by reacting the reaction solution containing the compound represented by formula (Vxe2x80x2) with a compound represented by formula R71-C(xe2x95x90O)xe2x80x94R72 (wherein R71 and R72 each independently represent a chlorine atom, 4-nitrophenyl, or 1-imidazolyl) including 1,1xe2x80x2-carbonyldiimidazole, phosgene, p-nitrophenyl chloroformate, or bis (p-nitrophenyl) carbonate, optionally in the presence of a base such as pyridine, to prepare a compound represented by formula (IIaxe2x80x2) wherein Q represents xe2x80x94OCOR71 (wherein R71 represents a chlorine atom, 4-nitrophenyl, or 1-imidazolyl) and then reacting the resulting compound with an alcohol represented by formula R33OH (wherein R33 is as defined above) The substituent Q may be further converted to another substituent.
(2) The compound represented by formula (IIaxe2x80x2) wherein Q represents group (ii) may be prepared by adding an acylating agent represented by R34COHal (wherein Hal and R34 are as defined above) or (R34CO)2O (wherein R34 is as defined above) to the reaction solution containing the compound represented by formula (Vxe2x80x2), optionally in the presence of a base such as pyridine.
The compound represented by formula (IIaxe2x80x2) wherein Q represents group (ii) may also be prepared by fusing the compound represented by formula (Vxe2x80x2) with a compound represented by formula R34COOH (wherein R34 is as defined above). Preferred condensing agents used herein include active esterifying agents such as dicyclohexylcarbodiimide, pyridine derivatives, and phosphoric acid derivatives, and dehydrating agents such as thionyl chloride and phosphorus oxychloride.
The compound may also be prepared by reacting the compound (IIaxe2x80x2) (wherein the substituent Q represents a halogen atom, which may be synthesized by a process described in process (4), with a sodium or potassium salt of a carboxylic acid represented by formula R34COOH (wherein R34 is as defined above) in a solvent which is not involved in the reaction in the presence of tetra-n-butylammonium bromide. Q may be further converted to another substituent.
(3) The compound represented by formula (IIaxe2x80x2) wherein Q represents group (iii) may be prepared by reacting the compound, produced in process (1), represented by formula (IIaxe2x80x2) (wherein R2 to R5, R31, R32, and R52 are as defined above and Q represents xe2x80x94OCOR71 (wherein R71 is as defined above)), optionally after isolation, with an amine represented by R35R36NH (wherein R35 and R36 are as defined above).
(4) The compound represented by formula (IIaxe2x80x2), wherein Q represents group (iv), a halogen atom, or C1-6 alkoxy, may be prepared by adding a chlorophosphoric ester represented by (R37O)(R38O)POCl, an alcohol represented by R73OH (wherein R73 represents C1-6 alkyl), or a halogenating agent such as thionyl chloride or thionyl bromide, to the reaction solution containing the compound (Vxe2x80x2). The reaction may be carried out generally at a temperature of xe2x88x9220 to 100xc2x0 C. for 0.1 to 48 hr.
All the compounds represented by formula (IIaxe2x80x2) synthesized by the process via the hemiacetal represented by the compound (Vxe2x80x2) are obtained as triazoles substituted at the 2-position.
 less than Process C greater than 
The compound represented by formula (IIaxe2x80x2), wherein Q represents group (i), may be prepared by reacting the compound represented by formula (V) with a compound represented by R31R32Cxe2x95x90O (wherein R31 and R32 are as defined above) (for example, isobutyl aldehyde) in an organic solvent such as acetone, acetonitrile, or ethyl acetate, at a temperature of xe2x88x9220 to 100xc2x0 C., preferably 22 to 28xc2x0 C., to prepare a compound represented by formula (Vxe2x80x2) and then reacting the compound represented by formula (Vxe2x80x2) in the same solution with a compound represented by HalCOOR33 (wherein Hal and R33 are as defined above) (for example, isopropyl chlorocarbonate), together with an alkali metal carbonate such as sodium carbonate or potassium carbonate, and an alkali metal iodide such as sodium iodide or potassium iodide, at 25 to 60xc2x0 C., post-treating the product, and crystallizing the treated product. Solvents used for the crystallization include lower alcohols, such as methanol, ethanol, and isopropyl alcohol. These solvents may be used together with water.
All the compounds represented by formula (IIaxe2x80x2) synthesized by this process are obtained as triazoles substituted at the 2-position. The above process is advantageous in that 1,1xe2x80x2-carbonyldiimidazole, which is expensive and unstable, is not used as the reactant, any by-product derived from 1,1xe2x80x2-carbonyldiimidazole is not produced, and the compounds represented by formula (IIaxe2x80x2) wherein Q represents the group (i) are obtained in high purity at high yield.
 less than Process D greater than 
The compound represented by formula (IIaxe2x80x2), wherein Q represents group (i), may also be prepared by directly reacting the compound represented by formula (V) with the compound represented by formula (IV) (for example, 1-chloro-2-methylpropyl-isopropyl carbonate).
More specifically, the compound represented by formula (V) may be reacted with the compound represented by formula (IV) in an organic solvent such as acetone, acetonitrile, ethyl acetate, or N,N-dimethylformamide, together with an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, or sodium hydroxide, and an alkali metal iodide such as sodium iodide or potassium iodide, at 25 to 60xc2x0 C. for 1 to 70 hr.
The compound represented by formula (IIaxe2x80x2) may be purified by conventional purification methods, for example, a solvent extraction, crystallization, or column chromatography on silica gel.
All the compounds represented by formula (IIaxe2x80x2) synthesized by the above process can be advantageously obtained as triazoles substituted at the 2-position. This seems to be due to the addition of the alkali metal iodide to the reaction system. The process is further advantageous in that the compounds represented by formula (IIaxe2x80x2) can be simply produced from the compound represented by formula (V) in a single step. An additional advantage of the process is that the formation of by-products derived from impurities contained in a ketone or an aldehyde (for example, isobutyric acid in isobutylaldehyde) represented by R31R32Cxe2x95x90O which is reacted with the compound represented by formula (V) in the process B and C can be avoided and high-purity compounds represented by formula (IIaxe2x80x2) can be obtained.
The compound represented by formula (IIa) may be produced by nitration of the compound represented by formula (VI). The nitration may be carried out in the presence of a nitrating agent such as (concentrated) nitric acid or fuming nitric acid without a solvent or in a solvent which is not involved in the reaction (for example, acetic anhydride, concentrated sulfuric acid, methylene chloride, or chloroform) at xe2x88x9210 to 50xc2x0 C. for 10 min to 24 hr.
The compound represented by formula (VI) may be prepared by introducing xe2x80x94CQR31R32 into the triazole group of the compound represented by formula (VII). The substituent xe2x80x94CQR31R32 may be introduced according to the process A, B. C, or D.
The compound represented by formula (VII) may be prepared by deprotecting the compound represented by formula (VIII).
The deprotection may be carried out according to a method described in D. R. Buckle and C. J. M. Rockell, J. Chem. Soc., Perkin Trans. I, 627 (1982), F. E. Nielsen, E. B. Pedersen, J. Heterocycl. Chem., 22, 1693 (1985). Specifically, when R61 represents a benzyl, diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 3,4,5-trimethoxybenzyl, benzyloxymethyl, or trimethylsilyl, the deprotection may be carried out by reacting the compound represented by formula (VIII) with a mineral acid such as dilute hydrochloric acid or dilute sulfuric acid, or an organic acid such as trifluoroacetic acid either as such or after dilution with a solvent which is not involved in the reaction (for example, methylene chloride or toluene) at 15 to 80xc2x0 C. for 1 to 24 hr.
The compound represented by formula (VII) may also be prepared by reacting the compound represented by formula (XII) with the compound represented by formula (XIIIxe2x80x2) in a solvent which is not involved in the reaction (for example, tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, or toluene) at xe2x88x9278 to 100xc2x0 C. for 15 min to 24 hr. The compound represented by formula (XIIIxe2x80x2) may be easily produced by reacting metal azide compounds such as sodium azide represented by formula (xxe2x80x2), various alkylsilyl azides, and various alkyltin azides, with an acetylenedicarboxylic diester.
The compound represented by formula (VII) may also be prepared by reacting the compound represented by formula (IX) with the metal azide compound represented by formula (Xxe2x80x2) in a solvent which is not involved in the reaction (for example, water, ethanol, isopropyl alcohol, tetrahydrofuran, diisopropyl ether, methylene chloride, acetone, toluene, ethyl acetate, N,N-dimethylformamide, or dimethylsulfoxide) at 0 to 120xc2x0 C. for 1 to 24 hr.
The compound represented by formula (VIII) may be prepared by reacting the compound represented by formula(IX) with the azide organic compound represented by formula (X) such as p-methoxybenzyl azide. The reaction may be carried out by a reaction of the compound represented by formula (IX) with the compound represented by formula (Xxe2x80x2).
The compound represented by formula (IX) may be prepared by reacting the compound represented by formula (XI) with chlorine, bromine, or iodine in a solvent which is not involved in the reaction (for example, water, ethanol, isopropyl alcohol, tetrahydrofuran, diisopropyl ether, methylene chloride, acetic acid, N,N-dimethylformamide, or dimethylsulfoxide) at xe2x88x9210 to 30xc2x0 C. for 10 min to 24 hr and then reacting the resultant halide with an organic base such as triethylamine, diisopropylethylamine, triisopropylamine, pyridine, picoline, lutidine, collidine, or quinoline, or an inorganic base such as potassium carbonate sodium carbonate, cesium carbonate, potassium hydrogencarbonate, or sodium hydrogencarbonate in the absence of a solvent or in a solvent which is not involved in the reaction (for example, water, ethanol, isopropyl alcohol, tetrahydrofuran, diisopropyl ether, methylene chloride, acetone, toluene, N,N-dimethylformamide, or dimethylsulfoxide) at 0 to 50xc2x0 C. for 1 to 24 hr.
The compound represented by formula (XI) may be prepared by a method described, for example, in Eur. J. Med. Chem., 23, 45 (1988) or U.S. Pat. No. 4,562,068.
The compound represented by formula (VIII) may also be prepared by converting a halo represented by formula (XIV) to an organometal compound represented by formula (XII) (for example, M represents lithium, magnesium chloride, magnesium bromide, magnesium iodide, zinc bromide, zinc iodide, cadmium bromide, cadmium iodide, copper or the like) and then reacting the compound represented by formula (XII) with the compound represented by formula (XIII) in a solvent which is not involved in the reaction (for example, tetrahydrofuran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, or toluene) at xe2x88x9278 to 100xc2x0 C. for 15 min to 24 hr. The compound represented by formula (XIII) may be easily prepared by reacting an azide compound (X) synthesized, for example, by a method described in J. Heterocyclic Chem., 21, 1669 (1984) with an acetylenedicarboxylic diester.
The compound represented by formula (V) may be prepared by deprotecting the compound represented by formula (XV). The deprotection may be carried out by the method described in connection with the deprotection of the compound represented by formula (VIII) to produce the compound represented by formula (VII).
The compound represented by formula (V) may also be produced by reacting the compound represented by formula (XVI) with the compound represented by formula (Xxe2x80x2). The reaction may be carried out by the method described above in connection with the reaction of the compound represented by formula (IX) with the compound represented by formula (Xxe2x80x2).
The compound represented by formula (V) may also be produced by nitrating the compound represented by formula (VII). The nitration may be carried out by the method described above in connection with the nitration of the compound represented by formula (VI) to produce the compound represented by formula (IIa).
The compound represented by formula (XV) may be produced by reacting the compound represented by formula (XVI) with the compound represented by formula (X). The reaction may be carried out by the method described above in connection with the reaction of the compound represented by formula (IX) with the compound represented by formula (X).
The compound represented by formula (XVI) may be produced from the compound represented by formula (XVII) by the method described above in connection with the production of the compound represented by formula (IX). from the compound represented by formula (XI).
The compound represented by formula (XVII) may be produced by a method described, for example, in Eur. J. Med. Chem., 23, 45 (1988) or U.S. Pat. No. 4,562,068.
The compound represented by formula (XV) may also be produced by nitrating the compound represented by formula (VIII). The nitration may be carried out by the method described above in connection with the nitration of the compound represented by formula (VI) to produce the compound represented by formula (IIa).
Further, the compound represented by formula (XV) may also be produced, for example, by a method described in WO 95/18130.
Oral administration of the compound represented by formula (I) according 1to the present invention to experimental animals have shown that the compound represented by formula (III) is detected in a higher concentration in plasma compared with administration of the compound represented by formula (III) alone. WO 95/18130 and WO 97/00258 disclose use of the compound represented by formula (III) as a therapeutic agent for allergic diseases. The compound represented by formula (I), after it is passed through various mucous membranes including digestive tracts, is converted in vivo to the compound represented by formula (III) which develops antiallergic activity.
The compound according to the present invention can be used as therapeutic agents for allergic diseases, for example, bronchial asthma, aczema, hives, allergic gastroenteritis, allergic rhinitis, and allergic conjunctivitis. The term xe2x80x9ctherapyxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d include xe2x80x9cpreventionxe2x80x9d or xe2x80x9cprophylaxis.xe2x80x9d
When orally administered, the compound according to the present invention may be formulated using conventional pharmaceutically acceptable excipients (for example, lactose, crystalline cellulose, starch, and calcium phosphate), binders (for example, starch, sodium carmellose, and hydroxypropylcellulose), disintegrators (calcium carmellose, calcium carbonate and the like), and lubricants (magnesium stearate, talc and the like) into tablets, capsules, granules, dry syrups, and various liquid preparations commonly used in medical treatment by conventional methods. Further, these various preparations may also be sustainedxe2x80x94release preparations which release the ingredient for a long period of time.
According to pharmacological activities including antiallergic action of the compound represented by formula (III), the compound according to the present invention may be applied to various treatments through administration routes other than oral administration. Dosage forms for this purpose include, but are not limited to, sublingual tablets, suppositories, inhalants, nasal drops, eye drops, and percutaneous absorption preparations, for example, patches or ointments/creams.
Although the content of the compound according to the present invention in the pharmaceutical composition depends on the preparations, it is generally in the range of from 1 to 70% by weight, preferably from about 5 to 50% by weight, based on the whole composition.
The dose for the treatment of allergic diseases may be appropriately determined individually in view of the direction for use, the age and sex of patients, the severity of symptoms and the like. In the case of oral preparations, sublingual tablets, or suppositories, however, the compound according to the present invention, or the salt or solvate thereof may be administered at a dose in the range of from 0.05 to 5 g/day, preferably 0.1 to 1.0 g/day, at one time or dividedly several times. Regarding other dosage forms, the dose may be properly increased or decreased depending on the intended use.